Project Summary/Abstract: Prior research efforts that focused on identifying the risks for Alzheimer's disease (AD) have not resulted in effective treatments. This led to a growing appreciation of resilience factors that allow individuals to remain disease-free despite having risk factors for AD. Centenarians are a population enriched with AD resilience, as many maintain normal cognition throughout their lifespan despite achieving advanced chronological age, a major risk factor for AD, or being carriers of high-risk AD associated genotypes. For over a decade our research group has focused on resilience factors that protect centenarians against AD and other age-related diseases by studying the genetically homogenous population of Ashkenazi Jews and has identified resilient genotypes that have been implicated in preservation of cognitive function. Building on our past success of multidisciplinary research and expanding our methodologies to include integrative network approaches we will test the hypothesis that individuals with exceptional longevity possess unique genotypes that result in resilience to dementia in two established longevity studies: (1) Longevity Genes Project (LGP), a cross sectional cohort of centenarians, who at age 95 had preserved cognitive function, and controls; (2) LonGenity, an independent, longitudinal study of offspring of centenarians, who are enriched with longevity genomes, and age-matched controls without parental history of longevity (planned n=1400, mean age 75) that are followed prospectively with neurocognitive assessments for the incidence of cognitive decline and AD. This proposal aims to integrate high-level data from these two longevity cohorts that includes genotypes, whole exome sequencing, biochemical, clinical and neurocognitive profiles and to interrogate it in an effort to identify cognitive resilience genes using: (1) gene-gene interaction analysis and (2) network-based integrative analysis. The top candidates discovered with these integrative approaches will be validated for their association with resilience in two human cohorts and in neuronal cell models that will be engineered to harbor the AD-resilience genotypes. By utilizing integrative computational approaches to analyze high-dimensional data, cell models, as well as validation cohorts, we aim to identify and validate genotypes and molecular networks that mediate cognitive resilience. Identification of these factors in resilient human populations has the potential to expedite the development of effective therapies for AD.